Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening, hereditary disease. The prevalence of ADPKD is more common than Huntington disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down syndrome combined. In recent years there have not only been advances in the understanding of the genetic and molecular events involved in ADPKD, but some diagnostic and therapeutic advances have also emerged. In the genetics area, the gene for PKD1 was localised to chromosome 16, is associated with polycystin-2 protein, and found to account for approximately 85% of patients with ADPKD. The gene for PKD2, found in chromosome 4, accounts for approximately 15% of ADPKD, and is associated with the polycystin-2 protein. While these genetic and molecular biology findings have stimulated a great deal of exciting basic research in ADPKD, therapies to decrease morbidity and mortality in ADPKD patients have yet to emerge from these findings. In contrast, the early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system have the potential to decrease or prevent left ventricular hypertrophy cardiac complications and slow the progression of the renal disease.
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PMID:Optimal care of autosomal dominant polycystic kidney disease patients. 1688 82

Mutations in the PKD1 and PKD2 polycystin genes are responsible for autosomal dominant polycystic kidney disease (ADPKD), one of the most prevalent genetic kidney disorders. ADPKD is a multisystem disease characterized by the formation of numerous fluid-filled cysts in the kidneys, the pancreas, and the liver. Moreover, major cardiovascular manifestations are common complications in ADPKD. Intracranial aneurysms and arterial hypertension are among the leading causes of mortality in this disease. In the present review, we summarize our current understanding of the role of polycystins in the development, maintenance, and function of the cardiovascular system.
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PMID:Cardiovascular polycystins: insights from autosomal dominant polycystic kidney disease and transgenic animal models. 1705 86

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2(WS25/-)). Four experimental groups (n = 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD.
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PMID:Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease. 1720 12

For determination of the incidence of renal events in autosomal dominant polycystic kidney disease (ADPKD) all patients who had ADPKD and attended nephrology/urology clinics in Newfoundland in 1981 were identified, and members of 18 families who were at 50% risk for inheriting ADPKD were followed prospectively for 22 yr, including research clinics at 6-yr intervals. Time to hypertension treatment, stage 3 chronic kidney disease (CKD), ESRD, and death was measured, and the impact of genotype, gender, gender of parent who transmitted PKD, family, family history of essential hypertension, parity, and oral contraceptive pill was assessed. Nine (50%) families had PKD1, four (22%) had PKD2, and one had both PKD1 and PKD2. The number of family members with PKD1 was 136 and with PKD2 was 60. In PKD1 median age to hypertension treatment was 46 yr, to CKD stage 3 was 50 yr, to ESRD was 53 yr, and to death was 67 yr. In PKD2, median age to hypertension treatment was 51 yr, to CKD stage 3 was 66 yr, to death was 71 yr, and ESRD was infrequent. Although the incidence of CKD was later and ESRD occurred infrequently in PKD2 compared with PKD1, early onset of hypertension occurred and life expectancy was compromised. Genotype, family, and proteinuria were identified as risk factors for incident renal events. Gender, gender of parent who transmitted PKD, family history of essential hypertension, multiparity, and use of the oral contraceptive pill were not identified as risk factors for renal events in ADPKD.
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PMID:Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population and family-based cohort followed for 22 years. 1769 77

Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder. However, the consequences of ADPKD on male and female reproductive health are not widely known. Several abnormalities are found in men with ADPKD, including necrospermia, immotile sperm, seminal vesicle cysts, and ejaculatory duct cysts. Female fertility is not affected. Affected women with ADPKD and normal renal function have a high rate of successful uncomplicated pregnancies. Pregnant women with ADPKD with compromised kidney function should be monitored carefully for the development of hypertension and preeclampsia. Their fetuses should be examined sonographically for signs of uteroplacental insufficiency, such as intrauterine growth restriction and oligohydramnios. The diagnosis of ADPKD should always be considered when prenatal sonographic findings of hyperechogenic enlarged kidneys are found. In this setting, a family history and renal sonogram of both parents is indicated. Sequencing of the PKD1 and PKD2 genes is available and can be used for both prenatal and preimplantation genetic diagnosis. We review in detail these topics to familiarize physicians taking care of patients with ADPKD with the reproductive issues that confront affected individuals.
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PMID:Reproductive issues for adults with autosomal dominant polycystic kidney disease. 1821 9

Adults with autosomal dominant polycystic kidney disease (ADPKD) and PKD1 mutations have a more severe disease than do patients with PKD2 mutations. The aim of this study was to compare phenotypes between children with mutations in the PKD1/PKD2 genes. Fifty PKD1 children and ten PKD2 children were investigated. Their mean age was similar (8.6 +/- 5.4 years and 8.9 +/- 5.6 years). Renal ultrasound was performed, and office blood pressure (BP), ambulatory BP, creatinine clearance and proteinuria were measured. The PKD1 children had, in comparison with those with PKD2, significantly greater total of renal cysts (13.3 +/- 12.5 vs 3.0 +/- 2.1, P = 0.004), larger kidneys [right/left kidney length 0.89 +/- 1.22 standard deviation score (SDS) vs 0.17 +/- 1.03 SDS, P = 0.045, and 1.19 +/- 1.42 SDS vs 0.12 +/- 1.09 SDS, P = 0.014, successively] and higher ambulatory day-time and night-time systolic BP (day-time/night-time BP index 0.93 +/- 0.10 vs 0.86 +/- 0.05, P = 0.021 and 0.94 +/- 0.07 vs 0.89 +/- 0.04, P = 0.037, successively). There were no significant differences in office BP, creatinine clearance or proteinuria. Prenatal renal cysts (14%), hypertension defined by ambulatory BP (27%) and enlarged kidneys (32%) were observed only in the PKD1 children. This is the first study on genotype-phenotype correlation in children with ADPKD. PKD1 children have more and larger renal cysts, larger kidneys and higher ambulatory BP than do PKD2 children. Renal cysts and enlarged kidneys detected prenatally are highly specific for children with PKD1.
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PMID:Genotype-phenotype correlation in children with autosomal dominant polycystic kidney disease. 1919 29

Cardiovascular complications such as hypertension are a continuous concern in patients with autosomal dominant polycystic kidney disease (ADPKD). The PKD2 encoding for polycystin-2 is mutated in approximately 15% of ADPKD patients. Here, we show that polycystin-2 is localized to the cilia of mouse and human vascular endothelial cells. We demonstrate that the normal expression level and localization of polycystin-2 to cilia is required for the endothelial cilia to sense fluid shear stress through a complex biochemical cascade, involving calcium, calmodulin, Akt/PKB, and protein kinase C. In response to fluid shear stress, mouse endothelial cells with knockdown or knockout of Pkd2 lose the ability to generate nitric oxide (NO). Consistent with mouse data, endothelial cells generated from ADPKD patients do not show polycystin-2 in the cilia and are unable to sense fluid flow. In the isolated artery, we further show that ciliary polycystin-2 responds specifically to shear stress and not to mechanical stretch, a pressurized biomechanical force that involves purinergic receptor activation. We propose a new role for polycystin-2 in transmitting extracellular shear stress to intracellular NO biosynthesis. Thus, aberrant expression or localization of polycystin-2 to cilia could promote high blood pressure because of inability to synthesize NO in response to an increase in shear stress (blood flow).
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PMID:Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. 1926 36

Autosomal dominant polycystic kidney disease is a multiorgan hereditary disorder. It is responsible for 7-10% of cases of end stage renal failure. It is caused by mutations in the genes PKD1 and PKD2. The diagnosis of this disease can be performed through ultrasounds, but the molecular diagnosis offers some advantages, such as the early detection of asymptomatic individuals who carry this genetic defect, in order to perform a preventive monitoring and genetic counselling. In this work, we present the results of the clinical analysis of 48 patients diagnosed with autosomal dominant polycystic kidney disease. The objectives of this work were to analyze the main clinical aspects of the disease. The average age of appearance of the first symptoms was 41.17 +/- 13.41 years in women and 49.91 +/- 12.52 years in men (p < 0.05). Arterial hypertension was the first sign of the disease (68.42%), with more cases in men than in women (p < 0.05), followed by chronic renal failure (68.29 %). The most common renal symptom during the evolution of the disease was chronic renal failure, which was present in all the patients of the study, followed by proteinuria (92.31%), end-stage renal failure (89.58%) and arterial hypertension (87.23%). In summary, our results reveal a high prevalence of patients with polycystic kidney disease who received a late diagnosis. This could possibly explain the high morbi-mortality associated to this condition. Given the high prevalence of chronic renal failure and endstage renal failure secondary to polycystic kidney disease in our study, the early diagnostic of the disease would carry better prognostic in relation with a more strict clinical followup. The arterial hypertension was the most frequent clinical manifestation of the disease in our study by what this entity should be included in all the hypertense patients of unknown etiology and on the other hand, the infectious complications should be a sign of alert in every patient with polycystic kidney disease.
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PMID:[Clinical analysis of a population with autosomal dominant polycystic kidney disease]. 2009 73

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies. Evidence implicates polycystin-1 (PC-1), the gene product of the PKD1 gene, in regulation of the mTOR pathway. Here we demonstrate a mechanism by which the intracellular, carboxy-terminal tail of polycystin-1 (CP1) regulates mTOR signaling by altering the subcellular localization of the tuberous sclerosis complex 2 (TSC2) tumor suppressor, a gatekeeper for mTOR activity. Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane, its GAP target Rheb, and its activating partner TSC1 to the cytosol via 14-3-3 protein binding. We found that TSC2 and a C-terminal polycystin-1 peptide (CP1) directly interact and that a membrane-tethered CP1 protects TSC2 from AKT phosphorylation at S939, retaining TSC2 at the membrane to inhibit the mTOR pathway. CP1 decreased binding of 14-3-3 proteins to TSC2 and increased the interaction between TSC2 and its activating partner TSC1. Interestingly, while membrane tethering of CP1 was required to activate TSC2 and repress mTOR, the ability of CP1 to inhibit mTOR signaling did not require primary cilia and was independent of AMPK activation. These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade.
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PMID:Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. 2016 78

Autosomal dominant polycystic kidney disease is a common disorder, affecting approximately one in 1,000 individuals. This disease is characterized by the presence of renal and extrarenal cysts, as well as by cardiovascular abnormalities, including hypertension and intracranial aneurysms. Mutations in the PKD1 gene account for 85% of cases, whereas mutations in PKD2 account for the remaining 15% of cases. Findings from the past 10 years indicate that polycystins, the products of the PKD genes, have a key role in renal and vascular mechanosensory transduction. In the primary cilium of renal, nodal, and endothelial cells, polycystins are proposed to act as flow sensors. In addition, the ratio of polycystin-1 to polycystin-2 regulates pressure sensing in arterial myocytes. In this Review, we summarize the data indicating that polycystins are key molecules in mechanotransduction. Moreover, we discuss the role of nucleotide release and autocrine and/or paracrine purinergic signaling in both fluid flow and pressure responses. Finally, we discuss the possible role of altered mechanosensory transduction in the etiology of polycystic kidney disease.
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PMID:Polycystins and renovascular mechanosensory transduction. 2062 75


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